targeted anticoagulation therapy to reduce inflammation and cellular activation in long-term hiv disease

Conditions: Inflammation; Coagulation; HIV Infection

Summary: the purpose of this study is to evaluate the effects of pharmacologic fxa inhibition (via edoxaban 30 mg daily) on inflammation, as reflected in plasma interleukin-6 levels.

we hypothesize that increased generation of activated factor x (fxa) contributes to a systemic elevation in pro-inflammatory cytokine levels (e.g. il-6) among hiv positive patients. this occurs, in part, via fxa activation of protease activated receptor 2 (par-2) on monocytes and tissue macrophages, which perpetuates innate inflammation. we will test our hypothesis with an oral antagonist to fxa (edoxaban), and quantify the immunologic effects of par-2 inhibition on systemic inflammation and monocyte activation. the potential benefits of pharmacologic inhibition of fxa will be studied among hiv positive participants receiving art with suppressed hiv viral load and a d-dimer \>100 ng/ml. the study design is a cross-over placebo controlled randomized trial of edoxaban 30mg daily versus matched placebo (n=40 total participants). after screening and baseline visits, participants will be randomized to the sequence of drug administration (i.e., edoxaban vs. placebo). after randomization, participants will start study medication #1 and follow-up for visits at months 1, 2, 3 and 4. they will then stop study medication for 3 months, return for visits at months 7 and 8 (analogous to screening and baseline, respectively), then start study medication #2 and follow-up for visits at months 9, 10, 11, and 12. the treatment effect (i.e., changes from pre-treatment levels) over 4 months will be assessed in measures of inflammation, immune activation, and coagulation. for comparisons with placebo, each participant will then serve as his or her own control in this cross-over design.

Eligibility criteria:
inclusion criteria * hiv infection (verified by previous positive antibody or detectable hiv rna level) * age ≥18 years * receiving continuous art for ≥2 years (regimen changes \>3 months prior to enrollment are acceptable) * hiv rna level ≤200 copies/ml for ≥1 year (1 measure ≥200 allowed if also \<500 and preceded and followed by one or more values ≤200 copies/ml) * d-dimer level ≥100 mg/l (or ng/ml) at screening (or within the prior month) * estimated creatinine clearance ≥50 ml/min * body weight ≥60kg * do not anticipate starting (or stopping) statin or aspirin therapy during the study * for women of child bearing potential, agrees to use a reliable form of birth control exclusion criteria * pregnancy or breast feeding * a contra-indication to taking edoxaban * a clinical indication for anticoagulation therapy (e.g., atrial fibrillation or deep vein thrombosis/pe) * treatment with anti-platelet, anti-coagulation, or immune-modulatory drugs currently or within the past 6 months; prior self-limited treatment with aspirin (i.e., not daily use) is not itself an exclusion. * grade ≥1 hematology lab abnormality for inr (\>1.1 x uln), hemoglobin (\<10.0 g/l), platelets (\<100,000 cells/μl), and wbc (2,500 cells/mm3) * grade ≥2 lab abnormality for chemistries (bmp) or liver panel * alcohol or illicit drug abuse/dependency within the prior year * history of prior myocardial infarction or unstable atherosclerotic disease * history of prior stroke or transient ischemic attack (tia) * history of active gastrointestinal ulcer or bleeding disorder within the prior year * intent to have surgery during the study period (12 months) * hepatitis c treatments (e.g., interferon, ribavirin, protease inhibitors) within the past 6 months * cirrhosis or hepatic impairment (e.g., child-pugh class b or c). * seizure disorder * previous/current cns space occupying lesion (e.g., toxoplasmosis, mtb) with persistent abnormalities on cns imaging after completion of treatment. * surgical or invasive procedure anticipated during study period. * invasive cancer in the prior year or receiving cancer treatment (not including carcinoma-in-situ or basal cell cancer of the skin) * rheumatologic or inflammatory disease, systemic in nature (e.g., systemic lupus erythematosus, rheumatoid arthritis, vasculitis, sarcoidosis, crohn's disease) * assessment by the clinical investigator that enrollment into the study could entail excess risk to the participant, beyond what is intended or expected.